Terpenes and terpenoids represent a large complex class of compounds built upon the isoprene unit, C5H8. Some terpenes and terpenoids have been used in the food, flavor and fragrance industries. Typically they are of plant or microbial origin and are often bound to tannins or glycosides.
Terpenes, which are important contributors to many fruit and floral scents, are synthesized from geranyl diphosphate (GDP), an intermediate in carotenoid biosynthesis. Monoterpene perillyl alcohol has been reported to inhibit photocarcinogenesis in a non-melanoma model of mouse skin carcinogenesis and UVB-induced skin carcinogenesis. Perillyl alcohol caused a reduction in UVB-induced non-melanoma tumors (Barthelman et al., Cancer Res. 1998; 58:711-716). Topical pretreatment but not post-treatment of the melanoma cells with perillyl alcohol markedly reduced levels of UV-induced reactive oxygen species. These studies suggest that perillyl alcohol inhibits the Ras signaling pathway and thus can be an effective target for chemoprevention of melanoma (Lluria-Prevatt et al., Cancer Epidemiology, Biomarkers & Prevention, 2002; 11(6):573-579).
Numerous studies have shown major changes in gene expression patterns associated with terpene exposure (Nakamura et al., FEBS Letters, 2004; 572(1-3): 245-250; Einbond et al., Anticancer Research, 2007; 27(2): 697-712; Rahman et al., Cancer Research, 2006; 66(9): 4952-4960). Very frequently gene expression changes involve clusters of genes directly or indirectly involved in lowering rates of cell proliferation, increasing antioxidative enzymes and increasing apoptosis. Some terpenes can act directly on epithelial cells in vitro and produce many of the same responses seen in vivo (Kim et al., Molecular Cancer Therapeutics, 2002; 1(3): 177-184). Some triterpenes exhibited cancer preventative capacity in breast, uterus, and lung cancer, respectively (Niwa et al., Oncology Reports, 2007; 17(3): 617-622; Liby et al., Cancer Research, 2007; 67(6): 2414-2419). Extract of a plant Rabdosia rubescens was reported to prevent cancer due to its content of diterpenoids (Ho et al., U.S. Pat. No. 7,351,739, 2008). Another plant extract from Acacia victoriae containing saponins suggested that it is the triterpenes which exhibited exhibit potent anti-tumor effects against a variety of tumor cells (Arntzen et al., US Patent Publication US2006/0073222 A1).
Kunsch et al., U.S. Pat. No. 7,247,714 suggests that certain compounds can activate cytoprotective response elements (CPREs) that have been identified to induce, coordinate and activate certain genes that protect cells from the potentially damaging effects of oxidative stress. CPREs have the DNA consensus sequence 5′-RTGACWNAGCANW-3′, wherein R=A or G, W=A or T, and N=A, G, C or T. The cellular functions of CPRE regulated genes are diverse, however in general, these genes act in various capacities to regulate and maintain redox homeostasis in the cell. The CPRE is unique, and different from the antioxidant response element (ARE) and the maf-recognition element (MARE).
d-Limonene is a cyclic monoterpene that can serve as a precursor to a host of other oxygenated monocyclic monoterpenes such as carveol, carvone, menthol, perillyl alcohol and perillaldehyde. It is characterized as a non-nutritive dietary component. d-Limonene is found in the essential oils of citrus fruits, cherry, mint and herbs. It is widely used in foods, flavors, fragrances, house hold products and skin cleansing formulation. d-Limonene is metabolized to oxygenated metabolites in rats and in humans. In rats, the two major serum metabolites of d-limonene are perillic acid and dihydroperillic acid. d-Limonene and its metabolites are detectable in serum, liver, lung and many other tissues with higher concentrations detected in adipose tissue and mammary gland than in less fatty tissues (Crowell et al., Cancer Chemother. Pharmacol. 1992; 31: 205-212). Humans produce these two serum metabolites as well as limonene-1,2-diol (Crowell et al., Cancer Chemother. Pharmacol. 1994; 35: 31-37). Metabolism of perillyl alcohol and d-limonene are similar.
Nootkatone is a sesquiterpene, present in grapefruit, tangerine, orange juices and oils. It does not appear to be toxic, at least at the concentrations found in normal strength grapefruit juice (approximately 0.0035%, or 35 ppm).
Norisoprenoid beta-damascenone is a widely used fragrance and flavor material present in a wide variety vegetables and teas. It is found also in grapes and wine either glycosylated or as an aglycon. Between 1 and 10 metric tons are used annually in the flavor and fragrance industry. No phototoxicity or photoallergenity has been reported in humans after topical application of beta-damascenone and UV-radiation. No skin irritation was observed in mice, guinea pigs and humans up to 5%. Higher concentration than 5% has not been tested. The LD50 was reported to be greater than 2.0 g/kg (Lapczynski et al., Food and Chemical Toxicology, 2007; 45(1): S172-S178).
Natural and synthetic vitamin A derivatives (retinoids) have been used extensively in the treatment of a variety of skin disorders and have been used as skin repair or renewal agents. Vitamin A is a diterpenoid. Compounds such as retinol occur naturally in the human body and are essential for normal epithelial cell differentiation. Retinoic acid, for example, has been used to treat a variety of skin conditions such as, for instance, acne, wrinkles, psoriasis, age spots and discoloration (Rollman, et al., Arch Dermatol Res., 1985a; 278(1):17-24 and Rollman, et al., Br J. Dermatol., 1985b; 113(4): 405-413; Lowe, et al., Pharmacol Skin 1989; 3:240-248). Although retinoids efficiently arrest the cell cycle of many types of epithelial tumors during the G1 stage, no single common mechanism of action has been identified. Retinal (preformed vitamin A) and/or certain carotenoids (provitamin A) are converted to retinol in the body, as needed. Retinol and the other retinoids are integrally involved in cell growth and differentiation, which may affect carcinogenesis, but retinoids often prove to be toxic at efficacious levels.
Vitamin C (L-ascorbic acid) has been described for use in topical administration to reinforce the cohesion of the dermo-epidermal junction (Bernerd, F. U.S. patent application Ser. No. 10/358,888, 2003). Pharmacologically, ascorbate ion is an antioxidant which is required as cofactor in collagen synthesis. Some studies suggested that ingestion of vitamin C rejuvenates skin. The same was observed with omega-6-linolenic acid.
The skin protects against external injuries such as wounding, UV radiation and microorganisms. It also is a water impermeable barrier against dehydration. The major barrier resides in the upper layer of the epidermis. This epidermis is continuously renewed. The basal keratinocytes are formed first in the proliferating layer stratum basale. These basal keratinocytes undergo terminal differentiation and become corneocytes in the outer layer of epidermis. This process is called cornification. Corneocytes reinforce their cytoskeletal keratin filament network in the stratum spinosum. Later these keratinocytes become more flat and express proteins such as profilaggrin and loricrin which aggregate and create keratohyalin granules of the stratum granulosum. At the final stage of differentiation the keratinocytes loose their nucleus and organelles and become dead. Protein profilaggrin is proteolytically modified in to filaggrin by Caspase 14. Fillagrin undergoes further proteolytic degradation with exo- and endo-proteases into hygroscopic amino acids which are responsible for the hydration of the skin. (Denecker et al., 2008) Another major protein of the cornified cell envelope of the terminally differentiated keratinocytes is loricrin which is eventually crosslinked to the keratin of the corneum. Loricrin contributes about 70% to the protein mass of the envelope cells, but is a minor percentage of the protein mass of the corneum (Candi et al., Nature Reviews Molecular Cell Biology 2005; 6: 328-340).
The skin renewal process relies on three events: (1) proliferation of new cells in the stratum basale, (2) cytoskeletal reinforcement in stratum spinosum and (3) differentiation of keratinocytes in stratum granulosum and stratum corneum. In the transitional layer between the stratum granulosum and the stratum corneum, lipids are extruded to form a water repelling envelope around the cornified envelope, thereby assuring an adequate permeability barrier function of the mammalian epidermis. Improper formation of these envelopes results in an impaired epidermal barrier that cannot protect against dehydration, UVB, and infection. Expression of late differentiation markers such as loricrin and filaggrin takes place at the end of the stratum granulosum. Expression of caspase 14 is crucial for proteolytic modification and degradation of profilaggrin. Caspase 14 is first expressed as procaspase 14 and it is activated at the interface between the granular and cornified layer. Once the profilaggrin is modified into fillaggrin, other proteases further process filaggrin into hygroscopic amino acids. Caspase 14 is also essential in protection against UVB-induced damage. How caspase 14 establishes UVB filtering capacity of the corneum is not completely understood.
The stratum corneum is the outermost layer of the epidermis, composed of large, flat, polyhedral, plate-like envelopes filled with keratin, which is made up of dead cells that have migrated up from the stratum granulosum. The stratum corneum is composed mainly of dead cells that lack nuclei. As these dead cells slough off on the surface in the thin air-filled stratum disjunctum, they are continuously replaced by new cells from the stratum germinativum (basale). In the human forearm, for example, about 1300 cells/cm2/hr are shed. This outer layer that is sloughed off is also known as the stratum dysjunctum. Cells of the stratum corneum contain keratin, a protein that helps keep the skin hydrated by preventing water evaporation. These cells can also absorb water, further aiding in hydration, and explaining why humans and other animals experience wrinkling of the skin on the fingers and toes (“pruning”) when immersed in water for prolonged periods. In addition, this layer is responsible for the “spring back” or stretchy properties of skin. A weak glutenous protein bond pulls the skin back to its natural shape.
The thickness of the stratum corneum varies according to the amount of protection and/or grip required by a region of the body. For example, the hands are typically used to grasp objects, requiring the palms to be covered with a thick stratum corneum. In a similar manner, the sole of the foot is prone to injury, and so it is protected with a thick stratum corneum layer. In general, the stratum corneum contains 15 to 20 layers of dead cells. The stratum corneum has a thickness between 10 and 40 μm.
The major proteins of the cornified cell envelope of the terminally differentiated keratinocytes are filaggrin, loricrin, keratin and other cornified envelope gene products, all of which are eventually crosslinked with the keratin of the corneum. Filaggrin, loricrin and other cornifying gene products contribute about 70% to the protein mass of the envelope, but the percentages may vary in the corneum (Candi et al., Nature Reviews Molecular Cell Biology 2005; 6: 328-340).
A VEGF, or vascular endothelial growth factor, that represents in the skin a major angiogenesis factor, is downregulated after UV-light exposure. Matrix metalloproteinases (MMPs) are enzymes that degrade the extracellular matrix in the context of physiological remodeling of the skin, but age and exposure to UV radiation have the effect of increasing the activity of these MMPs, in particular that of MMP1, MMP3 and MMP9.
UVR causes skin inflammation and redness (erythema) associated with sunburn. Sunscreen products typically applied in the form of a cream consist of active ingredients that adsorb UV-rays directly. Suitable sunscreens can have UVA absorbing properties, UVB absorbing properties or a mixture thereof. The exact amount of the sunscreen active ingredient may vary depending upon the desired Sun Protection Factor, i.e. the “SPF” of the composition as well as the desired level of UVR protection. SPF is a commonly used measure of photoprotection of a sunscreen against erythema. The SPF is defined as a ratio of the ultraviolet energy required to produce minimal erythema on protected skin to that required to produce the same minimal erythema on unprotected skin in the same individual (See, Federal Register, 43(166): 38206-38269, Aug. 25, 1978). Suitable sunscreens include, but are not limited to, those found in the CTFA International Cosmetic Ingredient Dictionary and Handbook, 7th edition, volume 2 pp. 1672, edited by Wenninger and McEwen (The Cosmetic, Toiletry, and Fragrance Association, Inc., Washington, D.C., 1997).
Suitable UVA absorbing sunscreen actives include, for instance, dibenzoylmethane derivatives, anthranilate derivatives such as methylanthranilate and homomethyl, 1-N-acetylanthranilate, and mixtures thereof. Examples of dibenzoylmethane sunscreen actives are described in U.S. Pat. No. 4,387,089 issued to Depolo; and in Sunscreens: Development, Evaluation, and Regulatory Aspects edited by N. J. Lowe and N. A. Shaath, Marcel Dekker, Inc (1990). These are all UVR absorbing type of sunscreen providing broad-spectrum UVA protection either independently, or in combination with, other UV protective actives that may be present in the composition.
Terpenes display some very interesting properties related to cancer prevention (Morita et al., Immunological Reviews 2007; 215: 59-76; Liby et al., Cancer Research, 2007; 67(6): 2414-2419; Niwa et al., Oncology Reports, 2007; 17(3): 617-622; Sengottuvelan et al., Carcinogenesis, 2006; 27(5): 1038-1046). Their relative safety makes them suitable for use in flavors and fragrances. Sometimes stereo-isomers of the same terpene have entirely different sensory profiles. Carvone is an example: 4R-(−)-carvone exhibits sweet spearmint flavor, whereas 4S-(+)-carvone tastes like caraway. Terpenes also tend to exhibit relatively high hydrophobicity and some are perceived as bitter to humans. Hydrophobicity allows terpenes to interact directly with cell membranes to trigger responses, such as greater level of anti-oxidation and apoptosis. Terpenes such as limonene, farnesol, geraniol and nerolidol have been suggested to enhance transdermal and transmucosal drug delivery (e.g. Aqil et al., Drug Discovery Today 2007; 12(23-24): 1061-1067). The penetration of terpenes is linked to their size, hydrophobicity, chirality, saturation and boiling point.
It seems that the receptor sites for bitter substances on the taste cells tends to be hydrophobic (Katsuragi et al., Biochim Biophys Acta 1996; 1289: 322-328) and may provide a mechanism whereby terpenes can interact directly with cell membranes to trigger responses, such as greater levels of anti-oxidation and apoptosis. Two additional important characteristics of terpene flavors are intensity and threshold concentration which are determined by the specificity of receptors (Ruiz et al., Chemical Senses 2006; 31(9):813-820). Terpenes are useful as skin penetration enhancers and agents involved in the prevention and therapy of inflammatory diseases. Some terpenes are better at preventing cancer than others and some can extend lifespan in lower organisms in addition to preventing cancer. Activity generally tends to increase with the order of polyterpenes and also hydroxylation (Crowell et al., Carcinogenesis 1992; 13(7): 1261-1264). Because of variable tastes and taste intensities and documented utility as dietary inhibitors of carcinogenesis, the huge variety of available terpenes provides a fertile field for establishing how they might be useful in sunburn protection and cancer prevention (Dragsted et al., Pharmacology & Toxicology 1993; 1: 116-135; Craig, American J. Clinical Nutrition 1999; 70(3): 491-499; Ray, Indian J. Cancer, 2005; 42(1): 15-24). Several terpenes have been established as cancer prevention agents in mice. Initiation of breast cancer induced by ionizing radiation or DMBA in rats was almost completely prevented by the monoterpene d-limonene and its hydroxylated derivative, perillyl alcohol, without any evidence of toxicity, and both agents were effective therapeutically as well (Crowell et al., Carcinogenesis 1992; 13(7): 1261-1264; Gould, J. Cell. Biochem. 1995; 22: 139-144). Geraniol was about 5-fold more effective than perillyl alcohol against the growth of human transplanted pancreatic adenocarcinomas (Burke et al., Lipids 1997; 32(2): 151-156).
A triterpene, actein, exhibited a synergistic therapeutic effect with 5-fluorouracil (a cancer chemotherapeutic agent) against human breast cancer cells in vitro apparently by causing increased apoptosis (Einbond et al., Planta Medica 2006; 72(13): 1200-1206). The synthetic triterpene 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) at nanomolar concentrations exhibited potent antiproliferative, pro-differentiation, and anti-inflammatory activities and large increases in the cytoprotective heme oxygenase-1 (HO-1) enzyme in vitro and in vivo. A similar inhibition of mouse lung tumors was noted based on anti-oxidative activity. (Liby et al., Cancer Research 2005; 65(11): 4789-4798; Liby et al., Cancer Research 2007; 67(6): 2414-2419). Mechanistic studies have found that triterpenes are strongly pro-apoptotic for human small cell lung cancer cells in vitro and act by blocking NF-KappaB thereby elevating apoptosis (Shishodia et al., Clinical Canc. Res. 2006; 12(6):1828-1838; Kim et al., Molecular Cancer Therapeutics 2002; 1(3): 177-184).
Numerous studies have shown major changes in gene expression patterns associated with terpene exposure (Nakamura et al., FEBS Letters 2004; 572(1-3): 245-250; Einbond et al., Anticancer Research 2007; 27(2): 697-712; Gould, M. N. Enciron. Health Perspectives 1997; 105: Suppl, 977-979; Rahman et al., Cancer Research 2006; 66(9): 4952-4960). Very frequently gene expression changes involve clusters of genes directly or indirectly involved in lowering rates of cell proliferation, increasing antioxidative enzymes and increasing apoptosis; all of which tend to block neoplastic growth. Several key genes that recur often in these studies are survivin, NFKappaB, TRAF, bcl-2 and IAP-2 (Shishodia et al., Clin. Canc. Res. 2006; 12(6): 1828-1838). Colon cancer induced in rats by 1,2-dimethylhydrazine was inhibited 67% (p<0.01) by 8 mg/kg of the phytoalexin, resveratrol (Sengottuvelan et al., Carcinogenesis 2006; 27(5): 1038-1046). Other studies show that hydrophobic receptors may play a role in causing apoptosis of cancer cells. Hydrophobic statins induced apoptosis and/or growth arrest in HCT116 cells (Powell et al., Biochem. J. 2001; 356: 481-486) and the cytotoxicity of various organic compounds against ovarian cancer cells was correlated with their hydrophobic and steric properties (Verma et al., 2006; 3(4): 441-450).
Hypotheses proposed to explain the cancer preventive activity of terpenes are generally variations on 1) altered cell signaling through gene expression changes, 2) antioxidative activity and 3) pro-apoptosis effects (Niwa et al., Oncology Reports 2007; 17(3): 617-622; Shishodia et al., 2006; 12(6): 1828-1838; Einbond et al., Anticancer Research 2007; 27(2): 697-712; Pusztai et al., Anticancer Research 2007; 27(1A): 201-205; Duarte et al., Planta Medica 2006; 72(2): 162-168). Monoterpenes are known to inhibit the isoprenylation of small G proteins which affects signal transduction and alters gene expression and can affect the cell cycle (Gould, Environ. Health Perpsectives 1997; 105: 977-979). Studies of mammary cancer show a series of effects including blockage of the G1 phase of the cell cycle, followed by apoptosis, redifferentiation, and frequently complete tumor regression (Gould, Environ. Health Perpsectives 1997; 105: 977-979; Crowell J. Nutrition 1999; 129(3): 775-778). The theme that terpenes can activate apoptosis and can have antioxidative and anti inflammatory activity is recurrent in the literature (Ray, Indian Journal of Cancer 2005; 42(1): 15-24; Wei et al., Carcinogenesis 1993; 14: 1195-1201). For example, quercetin and omega-3-fatty acids in colorectal and prostate cancer responded to the terpene, lycopene (Lambert et al., Am. J. Clin. Nutr. 2005; 81(1): 284-291). Others have found that the pyrophosphorylated isoprenoid intermediates and their metabolites are involved in the activation of the Vgamma2Vdelta2 T cells (Morita et al., Immun. Reviews 2007; 215: 59-76), which enhances the removal of tumor cells because of better recognition by T-cells and natural killer receptors. Additionally, hydrophobicity and steric parameters of the terpenes may be one of the most important determinants of cytotoxic activity (Verma et al., Molec. Pharm. 2006; 3(4): 441-450). Some synthetic triterpenes are strong inhibitors of inflammatory processes like induction of nitric oxide synthase (iNOS) and COX2 but also elevate phase 2 responses, including heme oxygenase 2 via the Nrf2-Keap1 signaling pathway (Dinkova-Kostova et al., PNAS 2005; 102(12): 4584-4589).
Atopic dermatitis may be the most prevalent dermatological disease for which no fully effective cure currently exists and apparently affects many millions worldwide. The cause of atopic dermatitis is unknown, some suggest that it is a failure of the skin restorative mechanisms, others inflammation or allergenic reaction. Although it is clear that the restoration of the barrier function of the skin would provide multiple benefits, including, sunburn protection, reversal of atopic dermatitis, dehydration protection, etc., the skin with atopic dermatitis needs moisture retention in the epidermal layer. The loss of barrier allows the skin to become very dry, which reduces its protective abilities. In addition, the skin is very susceptible to recurring disorders, such as staphylococcal and streptococcal bacterial skin infections, warts, herpes simplex, viral molluscum contagiosum, etc.
Human epidermal differentiation complex (EDC) comprises of several gene families: (1) the family of fused genes encoding filaggrin itself and filaggrin-like proteins (repetin, trichohyalin, cornulin and hornerin), (2) gene cluster with at least of 11 members (loricrin, involucrin and a small proline-rich region proteins), (3) S100 family genes, with at least 14 transcripts encoding calcium-binding proteins (11 of them are expressed in human epidermis). During the physiological formation of the cornified envelope, several genes from each family are expressed in a coordinated way and the epidermal barrier activity is acquired in a stepwise manner, firstly with involucrin expression, followed by the expression of 5100 proteins as well as small proline-rich region proteins and, finally, loricrin and filaggrin as late differentiation markers (Takaishi et al., 2005; J. Biol. Chem. 280:4696-4703).
Abnormal epidermal differentiation is observed in the dermatological diseases. Sagiura et al., 2005; British Journal of Dermatology 152:146-149 concluded that a key abnormality in atopic dermatitis might be due to the deterioration of epidermal differentiation associated with altered expression of genes located on chromosome 1q21. Metaphysical analysis of public microarray databases for different skin diseases suggested that there are seven commonly up-regulated genes, DSG3, KRT6, MAP17, PLSCR1, RPM2, SOD2 and SPRR2B. MAP17 is connected with the PDZK1 gene where the atopic dermatitis-linked region on human chromosome 1q21 is localized. MAP17 is significantly up-regulated in response to interferon-gamma or interleukin 4 in normal human epidermal keratinocytes. (Noh et al., 2010; Experimental Dermatology 19(4):355-62) Over-expression of MAP17 in HaCaT keratinocytes significantly decreased the expression of filaggrin. It appears that MAP17 is involved in the regulation of the expression of cornified envelope-associated genes at the 1q21 locus, such as filaggrin, loricrin and involucrin, It appears that the T-cell helper cytokine induces the up-regulation of MAP17 expression that is linked to the down-regulation of filaggrin in normal human epidermal keratinocytes, which may be associated with the abnormal epidermal differentiation observed in the dermatological diseases. (Noh et al., 2010; Experimental Dermatology 19(4):355-62) Theloricrin expression level was reported to be significantly decreased in chronic lesional atopic dermatitis skin along with deregulated increase in small proline-rich region proteins (SPRR) 1A and 2C. (Jarzab et al., 2010; International Archives of Allergy & Immunology 151(1):28-37) Late cornified envelope family of genes (e.g. LCE3B and LCE3C) expression can be induced in normal epidermis by skin barrier disruption and is strongly expressed in psoriatic lesions, suggesting that compromised skin barrier function has a role in psoriasis susceptibility. (de Cid et al., 2009; Nature Genetics 41: 211-215)
U.S. Patent Publication 2007/071839 teaches that an inflammatory disease such as atopic dermatitis or acne can be topically treated with composition containing terpenes from Ginko Biloba, fluoroglucinols from Humulus lupulus, and lipophilic compounds enriched in isobutylamides and other natural extracts. Another example of efficacy of monoterpene perillyl alcohol against the formation and progression of photocarcinogenesis indiced by UVB in mice was described by Barthelman et al., Cancer Res. 1998; 58:711-716. U.S. Patent Publication 2010/03052142 A1 by D'Alessio indicates that the topical application of monoterpenes was effective to repair tissue as an anti-inflammatory agent in a variety of skin diseases such as atopic dermitits, seborrheic keratitis, epidermolysis bullosa acquisita, psoriasis, skin alterations in lupus erythematosus, dermatomyositis, scleroderma, chronic acne, chronic cellulites, pruritus and abnormal or defective scar formation in diabetes. In their example limonene and perillyl alcohol, administered topically in a preventive treatment during 3 days at 10 mg/kg/day before the induction of skin inflammation, showed a significant effect on skin inflammation by reducing the inflammation degree (macroscopic and microscopic scores) and by reducing the pro-inflammatory cytokines secretion (IL-1Φ, IL-6 et TNF-α). Chaudhari (U.S. Patent Publication 2009/0036545 A1) teaches that meroterpenes (Sytenol A) act similarly to retinoic acid. Meroterpenes and retinoic acid help with skin rejuvenation, wrinkle control, skin aging through the effect on gene expression, in particular genes associated with retinoid acid receptors (RAR), dermal-epidermal junction and inflammation e.g. metalloproteinase MMP28, collagen alpha-6 precursor (COL4A6), heparin sulfotransferase (HS3ST1), lecithin retinol acetyltransferase (LRAT), cytochrome P450, some adherins, cytokeratins, etc.